The development of tolerance to nicotine parallels, and may be causally linked to the development of dependent smoking behavior. Understanding the mechanisms that underlie tolerance is thus an important step in understanding drug taking behavior. While it was once thought that tolerance depended exclusively on repeated drug exposure per se, it is now clear that learned associations with environmental cues that predict drug delivery can influence the tolerance process for a number of drugs. Thus chronic tolerance can include both environment-dependent and drug-dependent components. Recently, this laboratory has demonstrated that tolerance to the behavioral and endocrine effects of nicotine in rats also includes a learned component, and, that an anticipatory release of corticosterone (CORT), conditioned to environmental cues that signal drug delivery, may participate in this component of tolerance by reducing sensitivity to nicotine. Studies are planned to determine the contribution of this cue-triggered, anticipatory CORT response to the development of tolerance to the behavioral, endocrine and immunologic effects of nicotine. A method of drug delivery, intravenous infusion, will be used which increases greatly both the degree of control of drug-related cues and the temporal resolution of drug effects.